Signaling pathways drive cellular response, and understanding such pathways is fundamental to molecular systems biology. A mounting volume of experimental protein interaction data has motivated the development of algorithms to computationally reconstruct signaling pathways. However, existing methods suffer from low recall in recovering protein interactions in ground truth pathways, limiting our confidence in any new predictions for experimental validation. We present the Pathway Reconstruction AUGmenter (PRAUG), a higher-order function for producing high-quality pathway reconstruction algorithms. PRAUG modifies any existing pathway reconstruction method, resulting in augmented algorithms that outperform their un-augmented counterparts for six different algorithms across twenty-nine diverse signaling pathways. The algorithms produced by PRAUG collectively reveal potential new proteins and interactions involved in the Wnt and Notch signaling pathways. PRAUG offers a valuable framework for signaling pathway prediction and discovery.
It is widely assumed that in our lifetimes the products available in the global economy have become more diverse. This assumption is difficult to investigate directly, however, because it is difficult to collect the necessary data about every product in an economy each year. We solve this problem by mining publicly available textual descriptions of the products of every large US firms each year from 1997 to 2017. Although many aspects of economic productivity have been steadily rising during this period, our text-based measurements show that the diversity of the products of at least large US firms has steadily declined. This downward trend is visible using a variety of product diversity metrics, including some that depend on a measurement of the similarity of the products of every single pair of firms. The current state of the art in comprehensive and detailed firm-similarity measurements is a Boolean word vector model due to Hoberg and Phillips. We measure diversity using firm-similarities from this Boolean model and two more sophisticated variants, and we consistently observe a significant dropping trend in product diversity. These results make it possible to frame and start to test specific hypotheses for explaining the dropping product diversity trend.
A major goal of molecular systems biology is to understand the coordinated function of genes or proteins in response to cellular signals and to understand these dynamics in the context of disease. Signaling pathway databases such as KEGG, NetPath, NCI-PID, and Panther describe the molecular interactions involved in different cellular responses. While the same pathway may be present in different databases, prior work has shown that the particular proteins and interactions differ across database annotations. However, to our knowledge no one has attempted to quantify their structural differences. It is important to characterize artifacts or other biases within pathway databases, which can provide a more informed interpretation for downstream analyses. In this work, we consider signaling pathways as graphs and we use topological measures to study their structure. We find that topological characterization using graphlets (small, connected subgraphs) distinguishes signaling pathways from appropriate null models of interaction networks. Next, we quantify topological similarity across pathway databases. Our analysis reveals that the pathways harbor database-specific characteristics implying that even though these databases describe the same pathways, they tend to be systematically different from one another. We show that pathway-specific topology can be uncovered after accounting for database-specific structure. This work present the first step towards elucidating common pathway structure beyond their specific database annotations.
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